A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned
- PMID: 21729796
- DOI: 10.1016/j.spinee.2011.04.023
A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned
Abstract
Background context: Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight.
Purpose: To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases.
Study design: Systematic review.
Methods: Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses.
Results: There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy.
Conclusions: Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications.
Copyright © 2011 Elsevier Inc. All rights reserved.
Comment in
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A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors.Spine J. 2011 Jun;11(6):463-8. doi: 10.1016/j.spinee.2011.06.001. Spine J. 2011. PMID: 21729794 No abstract available.
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Resetting standards for sponsored research: do conflicts influence results?Spine J. 2011 Jun;11(6):492-4. doi: 10.1016/j.spinee.2011.05.001. Spine J. 2011. PMID: 21729797 No abstract available.
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Folly of FDA-approval studies for bone morphogenetic protein.Spine J. 2011 Jun;11(6):495-9. doi: 10.1016/j.spinee.2011.05.009. Spine J. 2011. PMID: 21729798 No abstract available.
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Acknowledging the elephant in the room: conflict of interest in industry-sponsored clinical research.Spine J. 2011 Aug;11(8):703-4. doi: 10.1016/j.spinee.2011.08.011. Spine J. 2011. PMID: 21925414 No abstract available.
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Re: A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.Spine J. 2011 Aug;11(8):804; author reply 804-5. doi: 10.1016/j.spinee.2011.08.001. Spine J. 2011. PMID: 21925424 No abstract available.
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Reply to "A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned".Spine J. 2011 Nov;11(11):1082-3; author reply 1083-6. doi: 10.1016/j.spinee.2011.09.029. Epub 2011 Nov 11. Spine J. 2011. PMID: 22078853 No abstract available.
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Letter to the editor regarding "A critical review of recombinant human morphogenetic protein-2 trials in spine surgery: emerging safety concerns and lessons learned".Spine J. 2012 Apr;12(4):356; author reply 356-7; discussion 357-9. doi: 10.1016/j.spinee.2012.03.005. Epub 2012 Mar 28. Spine J. 2012. PMID: 22464143 No abstract available.
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